The application of a new zinc-mediated carbenoid reaction to the preparation of peptide isosteres is described. This new method will be applicable to a wide variety of amino acid systems and will facilitate the preparation of inhibitors to a wide variety of viral proteases. The human cytomegalovirus (HCMV) serine protease is an attractive target and is specifically addressed in this study. Gamma-Keto esters which are incorporated into peptide skeletons have found great utility as mimics of a scissile peptide bond. These gamma-keto esters will be prepared from beta-keto esters in a single step through treatment with ethyl(iodomethyl)zinc. A two-step protocol is described in which beta-keto esters are incorporated into peptide fragments and then chain-extended to the corresponding gamma-keto esters. The preparation of a wide variety of peptide isosteric replacements should be possible through this methodology. A key feature of the study is the reactivity of the Reformatsky-like intermediate which will allow the incorporation of a variety of side chains that mimic the P1'-side chain of the peptide fragment. Stereocontrol of this side chain is essential to the full utilization of the zinc-mediated methodology. The application of this methodology to hydroxyethylene and difluoroketomethylene isostere systems is described. The approach to the difluoroketomethylene isostere is rapid and, if successful, will become the method of choice for the preparation of this isostere. The preparation of a novel isosteric system, gamma-keto phosphonates as part of an amino acid skeleton, is described. The relationship between peptide chemistry and solid-phase synthesis has continued to grow, mandating that methods which are proposed to impact peptide chemistry accommodate this relationship. The first practical approach to ketomethylene isostere generation on a solid support. Efforts will be made to incorporate this methodology onto a solid support in such a capacity as to make it compatible with peptide solid phase techniques.